?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F39981%2F&rft.title=Mechanisms+of+telomerase+inhibition+by+oxidized+and+therapeutic+dNTPs&rft.creator=Sanford%2C+Samantha&rft.description=Telomeres+cap+chromosome+ends+and+are+essential+for+genome+stability+and+human+health%2C+but+they+shorten+in+most+human+somatic+cells+with+cell+division+due+to+the+end+replication+problem.+Telomerase+a+specialized+reverse+transcriptase+that+lengthens+telomeres+by+adding+GGTTAG+repeats+to+chromosome+ends+and+is+upregulated+in+most+human+cancers+to+enable+limitless+proliferation.+Here%2C+we+uncover+two+distinct+mechanisms+by+which+naturally+occurring+oxidized+and+therapeutic+dNTP+DNA+precursors+inhibit+telomerase-mediated+telomere+elongation.+We+conducted+a+series+of+direct+telomerase+extension+assays+in+the+presence+of+modified+dNTPs+on+various+telomeric+substrates.+We+provide+direct+evidence+that+telomerase+can+add+the+metabolized+form+of+NRTIs%2C+dideoxyadenosine+5%E2%80%99+triphosphate+(ddITP)+and+3%E2%80%99-azido-3%E2%80%99deoxythymidine+triphosphate+(AZT-TP)%2C+to+the+telomeric+end%2C+causing+chain+termination.+In+contrast%2C+telomerase+continues+elongation+after+inserting+oxidized+2-OH-dATP+or+the+therapeutic+6-thioguanine+metabolite%2C+6-thio-dGTP%2C+but+insertion+disrupts+translocation+and+inhibits+further+repeat+addition.+Kinetics+reveal+that+telomerase+poorly+selects+against+6-thio-dGTP%2C+inserting+with+similar+catalytic+efficiency+as+dGTP.+Furthermore%2C+telomerase+processivity+factor+POT1-TPP1+fails+to+restore+processive+elongation+in+the+presence+of+inhibitory+dNTPs.+These+findings+reveal+mechanisms+for+targeting+telomerase+with+modified+dNTPs+in+cancer+therapy.&rft.date=2021-01-19&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F39981%2F7%2Fssanford%2520dissertation%2520final%252012%252017%252020.pdf&rft.identifier=++Sanford%2C+Samantha++(2021)+Mechanisms+of+telomerase+inhibition+by+oxidized+and+therapeutic+dNTPs.++Doctoral+Dissertation%2C+University+of+Pittsburgh.++++(Unpublished)++